Apparatus and method for indication of iontophoretic drug dispenser operability

ABSTRACT

An iontrophoretic medical device has a first light of controlled brightness. Iontophoretic contact with skin is measured by current flow and a second light is illuminated in proportion to current flow. Generally, equivalent brightness of the two lights indicates successful iontophoretic contact.

BACKGROUND OF THE INVENTION

Field of the Invention--This invention relates to indicators for thedegree of iontophoretic contact between iontophoresis device and theskin.

Priot Art--A number of devices have used iontophoresis for delivery ofdrugs through the skin. For example, the Medtronic CF indicator™ SweatTest employs iontophoresis to drive pilocarpine to the skin to inducesweat. The sweat is used in the test for cystic fibrosis.

Practitioners using sweat test devices need an indication of whensufficient sweat is collected so that a test can be accuratelyconducted. Many factors can influence amount of sweat produced duringthe iontophoretic application of pilocarpine. One of the mostinfluentical factors is the impedance of the interface between the skinand the drug delivery electrode. Skin impedance varies from patient topatient depending on factors such as race, age, skin condition, ormetabolic activity.

High skin impedance may often be dramatically lowered by a proper skinpreparation, such as scrubbing. The degree of need for such extrascrubbing varies among individuals. If a test fails due to the need forgreater skin preparation, it is advantageous to provide an indicatorwhich will alert the practitioner to the need for additional skinpreparation before the test is run.

Various methods have been tried to indicate to the operator the qualityof the contact. For example, the model 417 Skin Chloride MeasuringSystem produced by Orion Research includes an analog meter with a scaleto indicate a zone of appropriate skin impedance which is to be achievedbefore beginning the manual timing of iontophoretic drug delivery. Theneedle on the meter is read by the operator to determine when theapparatus may be used.

U.S. Pat. No. 4,109,645 by Bacchelli discloses an instrument formeasuring body resistance to ion flow after an established period whichallows for the stabilization of skin impedance. This device also givesan analog meter reading for the assessment of impedance.

The analog meters are to cumbersome for quickly indicating to anoperator of an iontophoretic device that proper skin preparation hasbeen achieved. Such methods add to the circuit complexity and cost ofthe device. In the testing for cystic fibrosis, a simple indication isneeded that sufficient sweat may be produced as the test is initiated.

SUMMARY OF THE INVENTION

An iontophoretic device constructed according to the present inventionincludes indicator lights to give a "go" condition indicative ofsufficient iontophoretic contact. A control light is provided whichserves a dual purpose. Illumination of the control light indicates thatadequate power supply voltage is present to power the iontophoretic drugdispenser. Secondly, the control light, when lighted, provides a presetcontrolled brightness. Means are provided for iontophoretic contact withthe skin. For example, this could be iontophoretic delivery of a drug.One example is the delivery of pilocarpine to generate sweat. Means areprovided to sense the quality of the iontophoretic contact, preferablyby sensing current flow across the skin impedance. Means are providedfor determining whether current flow at the skin impedance is adequate.A second light is illuminated in a gradually brightening fashion toindicate the quality of the current flow. As current flow indicates thatskin preparation is proper and iontophoretic delivery is achievable, asecond light is illuminated to generally equivalent brightness to thecontrol brightness of the first light.

The operator can easily determine by visual inspection of the first andsecond lights whether iontophoretic contact is sufficient. Thisindicator avoids the complex meter reading of the prior art systems andgives an indication which is easy to interpret. The operator of thedevice has an easy "go" or "no go" indication to use in deciding whetherdrug delivery is occurring in a satisfactory manner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an iontophoretic device having anindicator constructed according to the present invention;

FIG. 2 is a block diagram illustrating an embodiment of the presentinvention; and

FIG. 3 is a circuit diagram of the system of FIG. 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A device 10, as illustrated, includes indicator means constructedaccording to the present invention. Iontophoretic device 10 isillustrated mounted on a patient's arm 12 for iontophoretic delivery ofa drug through the skin. The particular drug delivery device illustratedis a Medtronic® CF Indicator™ Sweat Test device which deliverspilocarpine as the first step in a test. On the housing 14 of device 10are located a first LED or battery indicator light 16 and a second LEDor prep light 18.

The use of this sweat test device illustrates the present invention. Theskin of the patient is prepared by washing. The device 10 is thenstrapped to arm 12 and activated. If there is sufficient power to drivedevice 10, the first LED 16 lights up indicating that the device isoperable. First LED blinks on and off during iontophoretic drugdelivery.

The physician employing device 10 then inspects second LED 18. Ascurrent is conducted across the electrical load consisting of thepatient's skin, second LED 18 is illuminated. If skin impedance issufficiently low to allow proper operation of device 10, second LED 18is fully illuminated. The physican compares second LED 18 with first LED16 to determine that skin impedance is sufficiently low to perform atest. If second LED 18 is dimmer than first LED 16, the physician iswarned that skin impedance many be too high to perform a successfultest.

The normal procedure is then to remove device 10 from arm 12 and reprepthe skin. This usually entails scrubbing the area to allow cleanercontact with device 10. The device 10 is then restrapped to arm 12 andthe procedure of comparing second LED 18 to first LED 16 is repeated.

The electrical circuit of device 10 is schematically illustrated in FIG.2. Low battery indicator 20 includes circuitry for sensing voltage ofpower source 21 of device 10. Low battery indicator 20 controls theillumination of first LED 16 and indicates that there is sufficientpower to perform a test. Timing and control circuit 22 provides acontrol signal which is transmitted on line 24 to constant currentcircuit 26.

Constant current circuit 26 provides the electrical current to performiontophoresis on the skin of the patient which is represented by load28. The resistance across load 28 is in this example, the skin impedanceof the patient. LED 18 is in series with load 28 so that itsillumination depends upon the resistance of load 28.

Details of the circuit illustrated in the schematic of FIG. 2 are shownin FIG. 3.

Timing and control circuit 22 comprises 33 microfarad capacitor C1, 01microfarad capacitor C2, 1 megaohm resistors R1 and R2, NOR gates 30through 36, 910 kilohm resistor R5, 560 kilohm resistor R4, 0.056microfarad capacitor C3, 3.3. megohm resistor R3 and ripple counter U2.

Capacitor C1 is connected between ground and the positive 5 volt voltageterminal. This is a filter capacitor whose purpose is to reduce circuitnoise, and is not otherwise actively involved in the timing controlfunction. Capacitor C2 is connected between the high voltage side ofcapacitor C1 and the upper input terminal to NOR gate 30, which terminalis also connected to ground through resistor R1. NOR gates 30 and 32 arecoupled in a standard configuration for a flip-flop circuit. That is,the output of NOR gate 30 is connected to the upper input of NOR gate32, while the output of NOR gate 32 is connected to the lower input togate 30. The lower input to gate 32 is connected to the counter outputQ14 of ripple counter U2. The output of NOR gate 32 is also connected tothe two inputs of NOR gate 34. The lower input of gate 30 is alsoconnected to ground through resistor R2. The output of NOR gate 34 isconnected to the reset input R of ripple counter U2 and also to bothinputs of NOR gate 36. Resistors R4 and R5 are connected in parallelbetween pin 10 of ripple counter U2 and one side of capacitor C3, whichis also connected through resistor R3 to pin 11 of ripple counter U2.The other side of capacitor C3 is connected to pin 9 of ripple counterU2. Pin 8 of ripple counter U2 is connected to ground while pin 16 isconnected to the +5 volt power supply. Ripple counter U2 is a CD4060ripple counter divider available from RCA Solid State Division, Box3200, Summerville, N.J. 08876. The output of NOR gate 36 is applied toconstant current circuit 26 which is described below.

When the device is activated, the inputs to NOR gate 34 will be at alogic "0" since they are connected to ground through resistor R2, and nocurrent in initially flowing in the line. The output of gate 34 willthus be a logic "1" which resets ripple counter U2, setting the Q14output to a logic "0", and thus the lower input to gate 32 to a logic"0". At the same time a current will begin flowing in the circuitthrough resistor R1 to ground (charge will be building on capacitor C2)which will set the upper terminal to NOR gate 30 at a logic "1". Theoutput of gate 30 is thus forced to a logic "0" which is applied to theupper input of gate 32. The two inputs to gate 32 being a logic "0", theoutput will switch to a logic "1". This causes the output of gate 34 togo to a logic "0", which releases the reset on ripple counter U2, whichpermits it to begin counting, and at the same time causes the output ofgate 36 to switch from a logic "0" to a logic "1". While ripple counterU2 is counting the upper input to NOR gate 30 falls to a logic "0",however the output of the gate is maintained at a logic "0" because thelower input to the gate is held at a logic "1" as long as the lowerinput of gate 32 is held to a logic "0".

Ripple counter U2 is driven by oscillator circuit 38 consisting ofresistors R3, R4, R5 and capacitor C3. The value of resistor R5 isselected so that the oscillation period is 36.6 milliseconds. The ripplecounter will count the 36.6 milliseconds oscillations so that withinapproximately 5 minutes its fourteenth counter is triggered, and the Q14pin goes to a logic "1". This logic "1" signal applied to the lowerinput of gate 32 causes the output of the gate to go to a logic "0",which in turn forces the output of gate 34 to a logic "1", which holdsripple counter U2 reset and changes the output of NOR gate 36 to a logic"0". The logic "0" output of NOR gate 32 is also applied to the lowerinput of NOR gate 30. Both inputs of NOR gate 30 being a logic "0", theoutput will become a logic "1", which is applied to the upper input ofNOR gate 32 forcing its output to a logic "0" thereby latching gates 30and 32 in the "off" state such that the output of NOR gate 36 remains alogic "0" until the cycle is restarted. Thus, timing and control circuit22 provides a logic "1" signal to constant current circuit 26 for a5-minute period. While counter U2 is counting up to five minutes, itssixth counter stage will go to a logic "1" approximately every 2.3seconds. The output of the sixth counter stage (pin 4) will thus go to alogic "1" for a 1.15 second period every 2.3 seconds. This signal ispassed to low battery indicator circuit 20. When the counter has fullycounted the five minutes and gates 30 and 32 are latched into the "off"state all counter outputs will be at a logic "0" thus holding thevarious subcircuits in an off position as will be further describedbelow.

Constant current circuit 26 includes two constant current IN5290 diodesCR1 and CR2, 330 microfarad capacitor C5, 2N2222 transistor Q2, 2N4341FET Q3, 680 kilohm resistor R6 and 510 kilohm resistor R7.

The anode of constant current diode CR1 is connected to the output ofNOR gate 36 in timing and control circuit 22. The cathode of diode CR1is connected to the cathode of diode CR2 while the anode of diode CR2 isconnected to one side of capacitor C5 and also to the base of transistorQ2. The other side of capacitor C5 is connected to ground. The emitterof transistor Q2 is connected to the drain of FET Q3. The gate of FET Q3is connected to ground and is also connected to its own source throughparallel resistors R6 and R7. The collector of transistor Q2 isconnected to load 28.

When timing and control circuit 22 causes NOR gate 36 to go to a logic"1" state, a 5 volt signal is applied to the anode of diode CR1. Sincethis is a constant current diode the current that passes through it isfixed and thus the charge on capacitor C5 is built up slowly, over aperiod of about 1 second. Thus, the voltage applied to the base oftransistor Q2 builds up slowly, to the full 5 volt value over the sameperiod, causing the transistor to turn on slowly over the same period.FET Q3 and resistors R6 and R7 form a conventional current-limitingcircuit. Resistors are chosen to limit the current to 2 milliamps. Thus,upon application of the signal from timing and control circuit 22,constant current circuit 26 slowly, over a period of about a second,ramps up the current through its output line from 0 to a maximumconstant current of 2 milliamps. When, at the end of the 5-minuteperiod, the signal from timing and control circuit 22 drops to a logic"0", the charge on capacitor C5 will slowly drain throughcurrent-limiting diode CR2, again over about a 1-second period. Thus,the transistor Q2 will be slowly turned off over the same period and thecurrent through the output line will slowly ramp down to a 0 value.

Low battery indicator circuit 20 comprises 100 kilohm resistor R8,2N2222 transistor Q1, 2.2 kilohm resistor R9, LED CR3, an LM1OHdifferential amplifier U3, which is available from NationalSemiconductor Corp. at 29000 Semiconductor Drive, Santa Clara, CA 95051,820 kilohm resistor R10 and 12 kilohm resistor R11. The base oftransistor Q1 is connected to the Q6 output (pin 4) of ripple counter U2in timing and control circuit 22 through resistor R8. The collector oftransistor Q1 is connected to the positive 17 volt power source and toground through resistors R10 and R11. The emitter of transistor Q1 isconnected to the output (pin 6) of amplifier U3 through resistor R9 andLED CR3, and is also connected to pin 7 of amplifier U3. The value of R9is selected such that the current passing through it is equal to aminimum desired iontophoretic current level, which is 1.5 ma in thepreferred embodiment. Therefore, a current of 1.5 ma flows through LEDCR3 which causes CR3 to provide a reference brightness to which thebrightness of LED CR4 is visually compared. The negative input terminal(pin 2) of amplifier U3 is connected to the line between resistors R10and R11. The positive input terminal (pin 3) of amplifier U3 isconnected to both pin 1 and pin 8 of the same amplifier. The input pin 4of the amplifier U3 is connected to ground.

As discussed above, the Q6 output of ripple counter U2 in timing andcontrol circuit 22 will go to a logic "1" for a 1.15 second period onceeach 2.3 seconds while the counter is running. Each time it goes to alogic "1" transistor Q1 is turned on for the 1.15 second period providedthe battery level is above the predetermined level which for thisembodiment is 14 volts. The circuit consisting of amplifier U3,resistors R9, R10, and R11 and LED CR3 is a conventional battery-leveltest circuit disclosed in the applications manual for the U3 amplifierpublished by National Semiconductor Corporation.

When transistor Q1 turns on, it activates amplfier U3 which compares thevoltages between its negative and positive inputs. If the batteryvoltage is higher than 14 volts the amplifier connects its No. 6 pinoutput terminal to ground. This closes the circuit from the positiveterminal to ground through LED CR3, causing the LED to operate. If thebattery voltage is below 14 volts, amplifier U3 will not connect itsoutput (pin 6) to ground and LED CR3 will not turn on. Thus, Low BatteryIndicator Circuit 20 will cause LED CR3 to blink at 2.3 second intervalsduring the 5-minute period when the current is on, providing the batterylevel is above 14 volts.

Load 28 is illustrated as a resistor connected in series with constantcurrent circuit 26. PREP LED 18 (CR4) is connected in series between theload 28 and a 17 volt power source. A capacitor C4 is connected from the17 volt power source to ground.

The iontophoretic current flowing through load 28 is inverselyproportional to the magnitude of the resistive impedance of load 28.Since the load current must also flow through CR4, the brightness of CR4is therefore inversely related to the resistance in load 28. Abrightness of CR4 less than that of CR3 indicates current in load 28 ofless than desired minimum (1.5 ma) and indicates that load impedance isundesirably high. Brightness of CR4 equal to or greater than referencebrightness CR3 indicates that at least 1.5 ma iontophoretic current isbeing delivered to the load but not greater than 2.0 ma which iscontrolled by constant current circuit 26.

The present invention is useful in the operation of any iontophoreticdevice, since overcoming skin impedance is a major problem in successfuldrug delivery. While the invention has been illustrated in terms of atest device which iontophoretically drives pilocarpine into the skin, itis to be understood that this embodiment is not limiting as to the scopeof the present invention, but merely illustrative.

What is claimed is:
 1. A medical device for making iontophoretic contactwith skin of a patient comprising:a first visual indicator having afirst controlled indication level; means for making iontophoreticcontact with skin of a patient; means for measuring current flow acrossthe impedance of the patient's skin; a second visual indicator; meansfor activating the second visual indicator to a indication levelindicative of current flow across the impedance of the patient's skin,so that the indication level may be viually compared to the firstindication level.
 2. The device of claim 1 wherein the first visualindicator and the second visual indicator are lights.
 3. In a medicaldevice operating by iontophoretic contact with the skin, the improvementcomprising:a first control light which is constantly illuminated to acontrol brightness; means for making iontophoretic contact with skin ofa patient; means for measuring iontophoretic current flow across theimpedance of the patient's skin; and means electrically connected to themeans for sensing current flow for determining a level of satisfactorycurrent flow; a second indicator light; and means responsive to themeans for sensing current flow for illuminating the second light, suchthat a satisfactory level of current flow results in an illumination ofthe second light generally visually equivalent to the illumination ofthe first light.
 4. A method of iontophoretic treatment of a humanpatient comprising the following steps:providing a device for makingiontophoretic contact with the skin; providing a first light of aconstant control brightness; providing a second light electricallyconnected with the device for iontophoretic contact such that brightnessof a light indicates the quality of the contact with the skin; comparingthe brightness of the second light with the brightness of the firstlight; and determining, based upon general equivalence of the brightnessof the first and second lights that proper iontophoretic contact withthe skin has been achieved.